Mycobacterium tuberculosis (M.tb) disease remains an important life-threatening problem. While HIV infection clearly predisposes the infected patients to developing primary and reactivation tuberculosis, protective human immunity to M.tb is poorly understood. We have recently shown that the intravenous infection of macaques with Mycobacterium bovis Bacille Calmette-Guerin (BCG) induces potent CD4+ and CD8+ T cell responses, which are associated with the resolution of BCG infections. In contrast, the systemic BCG infection in SIV-infected monkeys results in the chronic co-infection and the development of disseminated BCG disease resembling tuberculosis. Based on the results showing the BCG-driven T cell responses, we hypothesize that MHC-restricted T cells exert anti-mycobacterial immunity against pulmonary mycobacterial infections in the infected individuals. The depletion or dysfunction of these T cell responses will, therefore, result in the increased susceptibility to primary mycobacterial infection or reactivation tuberculosis. To test this hypothesis, we have developed the macaque model of pulmonary BCG infection to characterize anti- mycobacterium T cells as well as to study BCG latency in the lungs. In addition, we have made use of systemic SIV/BCG co-infection to develop an in vivo system in which to test the role of antiretroviral therapy in restoring anti-mycobacterial immunity. Employing these model systems, we will: I. Identify anti-BCG T-cell responses in the lungs and determine the correlation between these responses and the resolution of active pulmonary BCG infection. II. Determine the impact of SIV-induced damage of anti-BCG T cell immunity on the reactivation of the latent pulmonary BCG infection. III. Determine the utility of antiretrovirals for restoring anti-BCG pulmonary T-cell immunity in SIV-infected monkeys.